Methods for treating urinary incontinence in mammals

ABSTRACT

Disclosed are methods for treating urinary incontinence in a mammal wherein a composition comprising a biocompatible polymer, a biocompatible solvent, and a contrast agent is delivered to the periurethral tissue of the mammal.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] This invention is directed to methods for treating urinaryincontinence in mammals generally and humans in particular. In thesemethods, a composition comprising a biocompatible polymer, abiocompatible solvent, and a contrast agent is delivered to theperiurethral tissue of a mammal.

[0003] The biocompatible polymer is selected to be soluble in thebiocompatible solvent, but insoluble in the periurethral tissue. Thebiocompatible solvent is miscible or soluble in the fluids of thistissue and, upon contact with such fluids, the biocompatible solventquickly diffuses away whereupon the biocompatible polymer precipitatesto form an occlusion in the periurethral tissue which compresses theurethra thereby preventing or reducing the involuntary leakage of urinefrom the bladder.

[0004] 2. References

[0005] The following publications are cited in this application assuperscript numbers:

[0006]¹ Murless, “The Injection Treatment of Stress Incontinence,” J.Obstet. Gynaecol., 45: 67-73 (1938).

[0007]² Quackels, “Deux Incontinences Après Adénomecomie Guéries ParInjection de Paraffine Dans Le Périnée,” Acta Urol. Belg., 23: 259-262(1955).

[0008]³ Sachse, “Treatment of Urinary Incontinence with SclerosingSolutions: Indications, Results, Complications,” Urol. Int., 15: 225-244(1963).

[0009]⁴ Politano. et al., “Periurethral Teflon Injection for UrinaryIncontinence.” J. Urol., 111: 180-183 (1974).

[0010]⁵ Lim, et al., “Periurethral Teflon Injection: A Simple Treatmentfor Urinary Incontinence,” Br. J. Urol., 55: 208-210 (1983).

[0011]⁶ Schulman, et al., “Endoscopic Injection of Teflon to TreatUrinary Incontinence in Women,” BMJ, 228: 192 (1984).

[0012]⁷ Rodriguez, “Late Results of the Endourethral Injection of Teflonin Stress Urinary Incontinence,” J. Urol. (Paris), 62: 39-41 (1987).

[0013]⁸ Vesey, et al., “Teflon Injection in Female Stress Incontinence.Effect on Urethral Pressure Profile and Flow Rate,” Br. J. Urol., 62:39-41 (1988).

[0014]⁹ Smart. “Poltef Paste for Urinary Incontinence,” Aust. N. Z. J.Surg., 61: 663-666 (1991).

[0015]¹⁰ Malizia, et al., “Migration and Granulomatous Reaction AfterPeriurethral Injection of Polytef (Teflon),” JAMA, 251: 3227-3281(1984).

[0016]¹¹ Stricker, et al., “Injectable Collagen for Type 3 Female StressIncontinence: The First 50 Australian Patients,” Med. J. Aust., 158:89-91 (1993).

[0017]¹² Moore, et al., “Periurethral Implantation of GlutaraldehydeCross-Linked Collagen (Contigen®) in Women with Type I or III StressIncontinence: Quantitative Outcome Measures,” Br. J. Urol., 75: 359-363(1995).

[0018]¹³ Capozza, et al., “Endoscopic Treatment of Vesico-UretericReflux and Urinary Incontinence: Technical Problems in the PediatricPatient,” Br. J. Urol., 75: 538-542.(1995).

[0019]¹⁴ Atala, et al., “Injectable Alginate Seeded with Chondrocytes asa Potential Treatment for Vesicoureteral Reflux,” J. Urol., 150: 745-747(1993).

[0020]¹⁵ Meriguerian, et al., “Submucosal Injection of Polyvinyl AlcoholFoam in Rabbit Bladder,” J. Urol., 144: 531-533 (1990).

[0021]¹⁶ Walker, et al., “Injectable Bioglass as a Potential Substitutefor Injectable Polytetrafluoroethylene,” J. Urol., 148: 645 (1992).

[0022]¹⁷ Atala, et al., “Endoscopic Treatment of Vesicoureteral Refluxwith a Self-Detachable Balloon System,” J. Urol., 148: 724-728 (1992).

[0023]¹⁸ Kinugasa, et al., “Direct Thrombosis of Aneurysms withCellulose Acetate Polymer”, J. Neurosurg., 77:501-507 (1992).

[0024]¹⁹ Kinugasa, et al., “Early Treatment of Subarachnoid HemorrhageAfter Preventing Rerupture of an Aneurysm”, J. Neurosurg., 83:34-41(1995).

[0025]²⁰ Kinugasa, et al., “Prophylactic Thrombosis to Prevent NewBleeding and to Delay Aneurysm Surgery”. Neurosurg., 36:661 (1995).

[0026]²¹ Greff, et al., U.S. patent application Ser. No. 08/508,248 for“Cellulose Diacetate Compositions for Use in Embolizing Blood Vessels”,filed Jul. 27, 1995.

[0027]²² Greff. et al., U.S. patent application Ser. No. 08/507,863 for“Novel Compositions for Use in Embolizing Blood Vessels”, filed Jul. 27,1995.

[0028]²³ Taki, et al., “Selection and Combination of VariousEndovascular Techniques in the Treatment of Giant Aneurysms”, J.Neurosurg., 77:37-42 (1992).

[0029]²⁴ Park. et al., “New Polymers for Therapeutic Embolization”,Poster #47, Meeting of Radiological Society of North America (1993)

[0030]²⁵ Winters. et al., “Periurethral Injection of Collagen in theTreatment of Intrinsic Sphincteric Deficiency in the Female Patient”,Urologic Clinics of North America, 22(3):473-478 (1995)

[0031] All of the above references are herein incorporated by referencein their entirety to the same extent as if each individual reference wasspecifically and individually indicated to be incorporated herein byreference in its entirety.

[0032] 3. State of the Art

[0033] Urinary incontinence is an extremely common problem especially inwomen. In particular, many women suffer from incontinence includingstress incontinence. In this condition, the pelvic-floor muscles whichsupport the base of the bladder and close off the top of the urethra areweakened by, for example, childbirth or obesity. As a result, whenpressure is exerted on these muscles by coughing, lifting, etc., urineis involuntarily discharged from the bladder through the urethra.

[0034] The initial treatment for stress incontinence typically consistsof exercises to strengthen the pelvic-floor muscles. If these exercisesare ineffective, open surgical repair of the bladder neck is oftenattempted. However, such surgical repair procedures are not successfulfor all patients. Moreover, there are always certain risks associatedwith open surgical procedures, such as trauma, infection, risks ofanesthesia, etc.

[0035] As an alternative to surgical repair, urinary incontinence hasbeen treated by injecting various substances into the tissue surroundingthe urethra, i.e., the periurethral tissue, to add bulk to this tissue.The aim of this treatment is to compress the urethra at the level of thebladder neck thus impeding the involuntary flow of urine from thebladder. Many substances have been tried for this purpose with varyingresults.

[0036] For example, Murless has reported the use of sodium morrhuate forthe treatment of stress incontinence.¹ However, this material was notsuccessful in preventing incontinence and pulmonary infarction wasobserved as a complication. Similarly, paraffin² and other sclerosingsolutions³ have been tried with poor results.

[0037] More recently, polytetrafluoroethylene particles (TEFLON™,POLYTEF™) have been used as an injectable material for the correction ofurinary incontinence with a success rate of from 30% to 86% in somestudies.⁴⁻⁹ However, these particles have subsequently been demonstratedto generate foreign body granulomas and to migrate to distant organs,such as the lungs, liver, spleen and brains Accordingly, the use ofpolytetrafluoroethylene particles is currently disfavored.

[0038] Another injectable material that has been used recently for thetreatment of urinary incontinence is glutaraldehyde cross-linked bovinedermal collagen. ¹¹⁻¹³ However, a major problem associated with the useof collagen materials is the tendency of the implant to decrease involume over time thereby necessitating retreatment.¹⁴ In addition,collagen has been associated with adverse immune responses and allergicreactions to bovine dermal collagen have been described.¹²

[0039] Various other injectable substances have been reported orproposed as implant materials for the treatment of bladder conditions,such as vesicoureteral reflux. These substances include polyvinylalcohol foam,¹⁵ glass particles,¹⁶ a chondrocyte-alginate suspension¹⁴and a detachable silicone balloon.⁷

[0040] In addition to the various problems associated with many of thesubstances used to treat urinary incontinence, the methods currentlyemployed for delivering injectable materials to the periurethral tissuehave certain disadvantages. In particular, the amount of materialnecessary to compress the urethra must typically be estimated byobserving the compression of the urethra wall using a cystoscope orendoscope. If an insufficient amount of material is injected in thefirst procedure, top-up injections administered in subsequent proceduresmay be necessary.¹¹ Accordingly, it would be advantageous to be able tomore accurately monitor the size of the occlusion formed by the injectedmaterial to ensure that it is sufficient to block the involuntaryleakage of urine from the bladder. Additionally, if follow-up injectionsare necessary, it would be advantageous to be able to locate accuratelythe site of the material previously injected.

[0041] In view of the above, it is evident that there is an ongoing needin the art for new methods of treating urinary incontinence in mammals.Preferably, such methods would allow an occlusion-forming substance tobe delivered accurately to the periurethral tissue. The substanceemployed would preferably conserve its volume in vivo, be non-migratoryand be substantially non-immunogenic.

[0042] This invention is directed to the discovery that urinaryincontinence can be treated in mammals by delivering sufficient amountsof a composition comprising a biocompatible polymer, a biocompatiblesolvent, and a contrast agent to the periurethral tissue underconditions such that a polymer precipitate forms in situ in theperiurethral tissue. This polymer precipitate compresses the urethralopening thereby affording increased outlet resistance and reducingurinary incontinence in the mammal. The polymeric compositions of thisinvention are non-biodegradable and, accordingly, do not substantiallydecrease in volume over time. Moreover, the injection process providesfor a coherent mass, not particulates, which mass is nonmigratory.Moreover, the contrast agent permits monitoring of the injection byconventional methods while it is taking place to ensure that it is beingcarried out properly. The contrast agent also allows monitoringpost-injection by conventional methods to ensure correct placement ofthe mass months or even years after injection. Conventional monitoringmethods include, by way of example, fluoroscopy, ultrasound, and in somecases visual detection.

SUMMARY OF THE INVENTION

[0043] This invention is directed to the discovery that unexpected andsurprising results are achieved when mammals with urinary incontinenceare treated with a composition comprising a biocompatible polymer, abiocompatible solvent, and a contrast agent. In particular, deficienciesassociated with the prior art procedures are reduced by the invention.Such deficiencies include, for example, problems associated withmigration of particulates over time, the biodegradation of the injectedmass (e.g., collagen type materials) employed to form an occlusion inthe periurethral tissue of the mammal, problems associated with theaccurate delivery of, such substances, and problems associated withpost-delivery monitoring of the deposited materials.

[0044] Accordingly, in one of its method aspects, this invention isdirected to a method for treating urinary incontinence in a mammal,which method comprises delivering a composition comprising abiocompatible polymer, a biocompatible solvent, and a contrast agent tothe periurethral tissue of the mammal

[0045] wherein said delivery is conducted under conditions such that apolymer precipitate forms in situ in the periurethral tissue therebyreducing the urinary incontinence in the mammal.

[0046] In another aspect of this invention, the use of a contrast agentis not required and the method is conducted by delivering a compositioncomprising a biocompatible polymer and a biocompatible solvent to theperiurethral tissue of the mammal

[0047] wherein said delivery is conducted under conditions such that apolymer precipitate forms in situ in the periurethral tissue therebyreducing, the urinary incontinence in the mammal.

[0048] However, the use of a contrast agent in the composition ispreferred.

[0049] The methods of this invention are preferably practiced using akit of parts comprising:

[0050] a first member which is a polymeric composition comprising abiocompatible polymer, a biocompatible solvent and a contrast agent; and

[0051] a second member-which is a needle selected from the groupselected of a puncture needle and spinal needle.

[0052] In the embolic compositions employed herein, the biocompatiblepolymer is preferably an ethylene vinyl alcohol copolymer or a celluloseacetate polymer. In a particularly preferred embodiment, thebiocompatible polymer is selected to be substantially non-immunogenic.

[0053] The biocompatible solvent is preferably dimethylsulfoxide and,more preferably, anhydrous dimethylsulfoxide.

DETAILED DESCRIPTION OF THE INVENTION

[0054] This invention is directed to methods for treating urinaryincontinence in mammals, which methods comprise delivering a compositioncomprising a biocompatible polymer, a biocompatible solvent, and acontrast agent to the periurethral tissue of the mammal.

[0055] Prior to discussing this invention in further detail, thefollowing terms will first be defined:

[0056] The term “urinary incontinence” refers to the involuntary leakageof urine through the urethra from the bladder. Methods for diagnosingurinary incontinence are well known to those skilled in the relevantart. Such methods included, for example, video urodynamics and pad testsas described by Moore, et al.¹²

[0057] The term “periurethral tissue” refers to the tissue surroundingthe urethra. As is understood in the art, the urethra is an orificeattached at its base to the bladder and permits discharge of urine fromthe bladder. Preferably, the polymeric compositions of the presentinvention are delivered to the periurethral tissue at or near the baseof the urethra.

[0058] The term “biocompatible polymer” refers to polymers which, in theamounts employed, are non-toxic, non-peptidyl, non-migratory, chemicallyinert, and substantially non-immunogenic when used internally in themammal and which are substantially insoluble in the periurethral tissue.The biocompatible polymers do not substantially decrease in volume overtime and, since the polymer forms a solid inert mass, it does notmigrate to distant organs within the body. Suitable biocompatiblepolymers include, by way of example, cellulose acetates ¹⁸⁻²⁰ (includingcellulose diacetate²¹), ethylene vinyl alcohol copolymers²²⁻²³,polyalkyl(C₁-C₆) acrylates, polyalkyl alkacrylates wherein the alkyl andthe alk groups contain no more than 6 carbon atoms, polyacrylonitrileand the like. Additional biocompatible polymers are disclosed in U.S.patent application Ser. No. 08/655,822 entitled “Novel Compositions forUse in Embolizing Blood Vessels” which application is incorporatedherein by reference in its entirety. Further examples of biocompatiblepolymers are provided by Park, et al.²⁴ Preferably, the biocompatiblepolymer is also non-inflammatory when employed in vivo.

[0059] The particular biocompatible polymer employed is not critical andis selected relative to the viscosity of the resulting polymer solution,the solubility of the biocompatible polymer in the biocompatiblesolvent, and the like. Such factors are well within the skill of theartisan.

[0060] Preferably, the biocompatible polymers do not appreciably absorbwater upon contact with the fluid of the periurethral tissue andtypically will have an equilibrium water content of less than about 25%water and preferably less than about 15% water.

[0061] Particularly preferred biocompatible polymers include cellulosediacetate and ethylene vinyl alcohol copolymer. Cellulose diacetatepolymers are either commercially available or can be prepared byart-recognized procedures. In a preferred embodiment, the number averagemolecular weight, as determined by gel permeation chromatography, of thecellulose diacetate composition is from about 25,000 to about 100,000;more preferably from about 50,000 to about 75,000; and still morepreferably from about 58,000 to 64,000. The weight average molecularweight of the cellulose diacetate composition, as determined by gelpermeation chromatography, is preferably from about 50,000 to 200,000and more preferably from about 100,000 to about 180,000. As is apparentto one skilled in the art, with all other factors being equal, cellulosediacetate polymers having a lower molecular weight will impart a lowerviscosity to the composition as compared to higher molecular weightpolymers. Accordingly, adjustment of the viscosity of the compositioncan be readily achieved by mere adjustment of the molecular weight ofthe polymer composition.

[0062] Ethylene vinyl alcohol copolymers comprise residues of bothethylene and vinyl alcohol monomers. Small amounts (e.g., less than 5mole percent) of additional monomers can be included in the polymerstructure or grafted thereon provided such additional monomers do notalter the occlusion-forming properties of the composition. Suchadditional monomers include, by way of example only, maleic anhydride,styrene, propylene, acrylic acid, vinyl acetate, and the like.

[0063] Ethylene vinyl alcohol copolymers are either commerciallyavailable or can be prepared by art-recognized procedures. Preferably,the ethylene vinyl alcohol copolymer composition is selected such that asolution of 6 weight percent of the ethylene vinyl alcohol copolymer, 35weight percent of a tantalum contrast agent in DMSO has a viscosityequal to or less than 60 centipoise at 20° C. As is apparent to oneskilled in the art, with all other factors being equal, copolymershaving a lower molecular weight will impart a lower-viscosity to thecomposition as compared to higher molecular weight copolymers.Accordingly, adjustment of the viscosity of the composition as necessaryfor catheter or needle delivery can be readily achieved by mereadjustment of the molecular weight of the copolymer composition.

[0064] As is also apparent, the ratio of ethylene to vinyl alcohol inthe copolymer affects the overall hydrophobicity/hydrophilicity of thecomposition which, in turn, affects the relative solubility of thecomposition in the biocompatible solvent as well as the rate ofprecipitation of the copolymer in an aqueous solution (e.g., plasma). Ina particularly preferred embodiment, the copolymers employed hereincomprise a mole percent of ethylene of from about 25 to about 60 and amole percent of vinyl alcohol of from about 40 to about 75. Morepreferably, these copolymers comprise from about 40 to about 60 molepercent of vinyl alcohol and from about 60 to 40 mole percent ofethylene. These compositions provide for requisite precipitation ratessuitable for treating urinary incontinence in mammals.

[0065] The term “contrast agent” refers to a biocompatible (non-toxic)radiopaque material capable of being monitored during injection into amammalian subject by, for example, radiography. The contrast agent canbe either water soluble or water insoluble, Examples of water solublecontrast agents include metrizamide, iopamidol, iothalamate sodium,iodomide sodium, and meglumine. Examples of water insoluble contrastagents include tantalum, tantalum oxide, and barium sulfate, each ofwhich is commercially available in the proper form for in vivo useincluding a particle size of about 10 μm or less. Other water insolublecontrast agents include gold, tungsten, and platinum powders.

[0066] Preferably, the contrast agent is water insoluble (i.e., has awater solubility of less than 0.01 mg/ml at 20° C.).

[0067] The term “biocompatible solvent” refers to an organic materialliquid at least at body temperature of the mammal in which thebiocompatible polymer is soluble and, in the amounts used, issubstantially non-toxic. Suitable biocompatible solvents include, by wayof example, dimethylsulfoxide, analogues/homologues ofdimethylsulfoxide, ethanol, acetone, and the like. Aqueous mixtures withthe biocompatible solvent can also be employed provided that the amountof water employed is sufficiently small that the dissolved polymerprecipitates upon contact with the periurethral tissue. Preferably, thebiocompatible solvent is dimethylsulfoxide.

[0068] Compositions

[0069] The polymer employed in the methods of this invention areprepared by conventional methods whereby each of the components is addedand the resulting composition mixed together until the overallcomposition is substantially homogeneous.

[0070] For example, polymer compositions can be prepared by addingsufficient amounts of the biocompatible polymer to the biocompatiblesolvent to-achieve the effective concentration for the polymercomposition. Preferably, the polymer composition will comprise fromabout 2.5 to about 8.0 weight percent of the biocompatible polymer basedon the total weight of the polymer composition, including contrast agentand biocompatible solvent, and more preferably from about 4 to about 5.2weight percent. If necessary, gentle heating and stirring can be used toeffect dissolution of the biocompatible polymer into the biocompatiblesolvent. e.g., 12 hours at 50° C.

[0071] Sufficient amounts of the contrast agent are then added to the-solution to achieve the effective concentration for the completepolymer composition. Preferably, the polymer composition will comprisefrom about 10 to about 40 weight percent of the contrast agent and morepreferably from about 20 to about 40 weight percent and even morepreferably about 35 weight percent each based on the total weight of thepolymer composition including the biocompatible polymer and thebiocompatible solvent. When the contrast agent is not soluble in thebiocompatible solvent, stirring is employed to effect homogeneity of theresulting suspension. In order to enhance formation of the suspension,the particle size of the contrast agent is preferably maintained atabout 10 μm or less and more preferably at from about 1 to about 5 μm(e.g., an average size of about 2 μm). In one preferred embodiment, theparticle size of a water insoluble contrast agent is prepared, forexample, by fractionation. In such an embodiment, a water insolublecontrast agent such as tantalum having a particle size of less thanabout 20 microns is added to an organic liquid such as ethanol(absolute) preferably in a clean environment. Agitation of the resultingsuspension followed by settling for approximately 40 seconds permits thelarger particles to settle faster. Removal of the upper portion-of theorganic liquid followed by separation of the liquid from the particlesresults in a reduction of the particle size which is confirmed under amicroscope. The process is optionally repeated until a desired particlesize is reached.

[0072] The particular order of addition of components to thebiocompatible solvent is not critical and stirring of the resultingsuspension is conducted as necessary to achieve homogeneity of thecomposition. Preferably, mixing/stirring of the composition is conductedunder an anhydrous atmosphere at ambient pressure. The resultingcomposition may be heat sterilized and then stored preferably in sealedbottles (e.g., amber vials) or vials until needed.

[0073] Methods

[0074] The compositions described above are then employed in methods fortreating urinary incontinence in mammals. In these methods, thecomposition is introduced to the periurethral tissue via conventionalcatheter or needle technology using, for example, cystoscopictechniques. Specifically, the injection may be performed through apuncture needle or spinal needle placed directly through the cystoscopeor periurethrally with a spinal needle placed percutaneously at theintroitus and positioned in the tissue adjacent to the urethra asdescribed by Winters, et al.²⁵ Alternatively, the periurethral tissuecan be exposed surgically and the composition injected directly into thetissue.

[0075] Upon discharge of the composition from the catheter or the needleinto the periurethral tissue, the biocompatible solvent dissipates intothe fluid of the periurethral tissue resulting in the precipitation ofthe biocompatible polymer which precipitate forms a coherent mass. Theformed precipitate in the periurethral tissue swells this tissuerestricting the urethral orifice thus impeding the involuntary flow ofurine from the bladder.

[0076] The particular amount of polymer composition employed is dictatedby the level of pre-existing support of the periurethral tissue, theconcentration of polymer in the composition, the rate of precipitation(solids formation) of the polymer, etc. Such factors are well within theskill of the artisan. For example, individuals with weak pre-existingsupport of the periurethral tissue will require injection of morepolymer composition in order to bulk up this tissue and constrict theurethra as compared to individuals with stronger pre-existing support.

[0077] The methods of this invention are particularly advantageousbecause the presence of the contrast agent in the composition permits,if desired, monitoring of the delivery of the biocompatible polymerwhile it is taking place either by fluoroscopy, ultrasound, or visually.In this way, one can ensure that the biocompatible polymer is beingdelivered to the optimal location in the periurethral tissue as well asdetermine whether the size of the polymer precipitate thus-formed willbe sufficient to block the involuntary leakage of urine from thebladder.

[0078] Moreover, the treatment process can be modified by altering therate of precipitation of the polymer which can be controlled merely bychanging the overall hydrophobicity/hydrophilicity of the polymer. As isunderstood in the art, faster precipitation rates are achieved by a morehydrophobic polymer composition.

[0079] When delivery of the polymeric composition to the periurethraltissue is conducted via a cystoscope used in combination with a smalldiameter medical catheter (which typically employs a needle as describedby Capozza, et al.¹³), the catheter employed is not critical providedthat polymeric catheter components are compatible with the polymericcomposition (i.e., the catheter components will not readily degrade inthe polymer composition and none of the components of the polymercompositions will readily degrade in the presence of the cathetercomponents). In this regard, it is preferred to use polyethylene in thecatheter components because of its inertness in the presence of thepolymeric composition described herein. Other materials compatible withthe composition can be readily determined by the skilled artisan andinclude, for example, other polyolefins, fluoropolymers (e.g.,polytetrafluoroethylene, perfluoroalkoxy resin, fluorinated ethylenepropylene polymers), silicone, etc.

[0080] When introduced into the periurethral tissue, the biocompatiblesolvent rapidly diffuses into the fluids of this tissue leaving a solidprecipitate. The precipitate is a coherent mass comprising a combinationof the biocompatible polymer and the contrast agent. Without beinglimited to any theory, it is believed that this precipitate bulks up theperiurethral tissue thereby increasing outlet resistance to urinary flowfrom the bladder. This enhanced outlet resistance reduces the urinaryincontinence in the treated mammal.

[0081] Another advantage of this invention is that the precipitate formsa coherent mass which is substantially retained at the site of injectionthereby obviating prior art concerns with migration of injectedparticulates into the periurethral tissue. Moreover, the polymericcompositions of this invention are non-biodegradable and, accordingly,do not substantially decrease in volume over time.

[0082] Still another advantage of this invention is that the polymeremployed can be selected to be non-immunogenic thereby obviatingconcerns raised by use of collagen-type materials which can produce animmune response in vivo.

[0083] Yet another advantage of this invention is the formation of apolymeric mass in the periurethral tissue which mass contains a waterinsoluble contrast agent that permits the physician to monitor theimplant over time to assure proper retention of the mass in the tissue.Additionally, if a subsequent injection is necessary to further reduceurinary incontinence in the mammal, placement of the additionalpolymeric material is facilitated when the material previously implantedcan be visualized by, for example, fluoroscopy, ultrasound, and thelike. A subsequent injection can occur at any time after the initialinjection including, for example, months or years later.

[0084] In view of the above, the methods of this invention arepreferably practiced using a kit of parts which kit contains a firstmember which is a polymeric composition comprising a biocompatiblepolymer, a biocompatible solvent and a contrast agent, and a secondmember which is a needle selected from the group consisting from apuncture needle and spinal needle.

[0085] Utility

[0086] The methods described herein are useful in treating mammals withurinary incontinence. Accordingly, these methods find use in human andother mammalian subjects requiring such treatment.

[0087] Additionally, it is contemplated that the compositions of thisinvention can be used to treat vesicoureteral reflux in a mammal. Inthis condition, urine from the bladder refluxes into a ureter oftencausing infection. It is contemplated the such reflux can be treated bydelivering a composition comprising a biocompatible polymer, abiocompatible solvent, and a contrast agent to the subureteral tissue ofthe mammal. This delivery would be conducted under conditions such thata polymer precipitate forms in situ in the subureteral tissue therebyreducing vesicoureteral reflux in the mammal. The formation of a polymerprecipitate in the subureteral tissue is expected to compress the ureterthereby reducing the reflux of urine into the ureter. Methods fordelivering the composition to treat vesicoureteral reflux are describedby Capozza, et al.¹³

[0088] The following examples are set forth to illustrate the claimedinvention and are not to be construed as a limitation thereof.

EXAMPLES

[0089] Unless otherwise stated, all temperatures are in degrees Celsius.Also, in these examples and elsewhere, the following abbreviations havethe following meanings: cc = cubic centimeter DMSO = dimethylsulfoxideEVOH = ethylene vinyl alcohol copolymer mL = milliliter mm = millimeterμm = micron

[0090] In the following examples, Examples 1-2 illustrate thepreparation of polymer compositions useful in the methods describedherein which polymer compositions comprise EVOH and cellulose acetate.Example 3 demonstrates the biocompatibility, non-migratory and bulkingproperties of an EVOH polymer in vivo.

Example 1

[0091] An EVOH polymer composition was prepared by combining 8 grams ofEVOH (44 mole percent ethylene), 30 grams of tantalum having an averageparticle size of about 3 μm (narrow size distribution), and 100 mL ofanhydrous DMSO. Heating at about 50° C. for about 12 hours was used toaid dissolution. The composition was mixed until homogeneous.

[0092] Tantalum having an average particle size of about 3 μm (narrowsize distribution) was prepared by fractionation wherein tantalum,having an average particle size of less than about 20 μm, was added toethanol (absolute) in a clean environment. Agitation of the resultingsuspension was followed by settling for approximately 40 sec. to permitthe larger particles to settle faster. Removal of the upper portion ofthe ethanol followed by separation of the liquid from the particlesresults in a reduction of the particle size which is confirmed under amicroscope (Nikon Alphaphot™). The process was repeated, as necessary,until an average 3 μm particle size was reached.

Example 2

[0093] A cellulose diacetate polymer composition is prepared bycombining 8 grams of cellulose acetate (39.7 weight percent acetylcontent), 30 grams of tantalum having an average particle size of about3 μm (narrow size distribution), and 100 mL of DMSO. The composition ismixed until homogeneous. Tantalum having an average particle size ofabout 3 μm (narrow size distribution) is prepared by fractionation asdescribed in Example 1.

Example 3

[0094] The purpose of this example is to demonstrate thebiocompatibility of an EVOH polymer with the bladder tissue of a mammaland to illustrate the non-migratory properties of such a polymer.Additionally, this example illustrates the ability of such a polymer toserve as a bulking agent in bladder tissue.

[0095] Female New Zealand white rabbits were utilized for thisinvestigation. Using a 26 gauge needle, several 0.5 cc injections of anEVOH polymer composition, prepared in a manner essentially the same asthat described in Example 1, were made submucosally in the bladder ofeach rabbit while the animals were under general anesthesia. Prior tosacrifice, x-rays were obtained to search for migration of the injectedmaterial. Two rabbits were sacrificed at one week post-injection and thebladders excised and examined histologically via 5 micronsectioning/staining of fresh-frozen and paraffin embedded tissue samplesof the injection sites and surrounding areas. The injection sites showedblack pigmentation (tantalum) with some inflammation and cellularinfiltration, i.e., a typical foreign body reaction. Tissues surroundingthe injection site were normal. The implant had not migrated andappeared as one coherent mass.

[0096] From the foregoing description, various modifications and changesin the composition and method will occur to those skilled in the art.All such modifications coming within the scope of the appended claimsare intended to be included therein.

What is claimed is:
 1. A method for treating urinary incontinence in amammal, which method comprises delivering a composition comprising abiocompatible polymer, a biocompatible solvent, and a contrast agent tothe periurethral tissue of the mammal wherein said delivery is conductedunder conditions such that a polymer precipitate forms in situ in theperiurethral tissue thereby reducing urinary incontinence in the mammal.2. The method according to claim 1 wherein said biocompatible polymer isselected from the group consisting of cellulose acetate polymers,ethylene vinyl alcohol copolymers and polyacrylates.
 3. The methodaccording to claim 2 wherein said biocompatible polymer is a celluloseacetate polymer or an ethylene vinyl alcohol copolymer.
 4. The methodaccording to claim 1 wherein said biocompatible solvent is selected fromthe group consisting of dimethylsulfoxide, ethanol, and acetone
 5. Themethod according to claim 4 wherein said biocompatible solvent isdimethylsulfoxide.
 6. The method according to claim 1 wherein saidcontrast agent is a water insoluble contrast agent.
 7. The methodaccording to claim 6 wherein said water insoluble contrast agent isselected from the group consisting of tantalum, tantalum oxide,tungsten, and barium sulfate.
 8. The method according to claim 1 whereinsaid contrast agent is a water soluble contrast agent.
 9. The methodaccording to claim 8 wherein said water soluble contrast agent ismetrizamide.
 10. The method according to claim 1 wherein saidcomposition is delivered into the periurethral tissue via a cystoscope.11. A method for the delivery of a composition comprising abiocompatible polymer, a biocompatible solvent, and a water insolublecontrast agent to the periurethral tissue of the mammal which tissuealready has deposited therein with an initial amount of this compositionwhich method comprises visualizing the position of the depositedcomposition in the periurethral tissue delivering a compositioncomprising a biocompatible polymer, a biocompatible solvent, and acontrast agent to the periurethral tissue of the mammal containing saiddeposited composition wherein said delivery is conducted underconditions such that additional polymer precipitate forms in situ in theperiurethral tissue thereby further reducing urinary incontinence in themammal.
 12. The method according to claim 11 wherein visualization isconducted by direct visualization, fluoroscopy or ultrasound.
 13. A kitof parts comprising: a first member which is an embolic compositioncomprising a biocompatible polymer, a biocompatible solvent and acontrast agent; and a second member which is a needle selected from thegroup consisting of a puncture needle and spinal needle.
 14. The kit ofparts according to claim 13 wherein said biocompatible polymer isselected from the group consisting of cellulose acetates, ethylene vinylalcohol copolymers, polyalkyl(C₁-C₆) acrylates, polyalkyl alkacrylateswherein the alkyl and the alk groups contain no more than 6 carbonatoms; and polyacrylonitrile.
 15. The kit of parts according to claim 14wherein said biocompatible polymer is a cellulose acetate polymer or anethylene vinyl alcohol copolymer.
 16. The kit of parts according toclaim 14 wherein said biocompatible solvent is selected from the groupconsisting of dimethylsulfoxide, ethanol, and acetone.
 17. The kit ofparts according to claim 16 wherein said biocompatible solvent isdimethylsulfoxide.
 18. The kit of parts according to claim 13 whereinsaid contrast agent is a water insoluble contrast agent.
 19. The kit ofparts according to claim 18 wherein said water insoluble contrast agentis selected from the group consisting of tantalum, tantalum oxide,tungsten, and barium sulfate.
 20. A method for treating urinaryincontinence in a mammal, which method comprises delivering acomposition comprising a biocompatible polymer and a biocompatiblesolvent to the periurethral tissue of the mammal wherein said deliveryis conducted under conditions such that a polymer precipitate forms insitu in the periurethral tissue thereby reducing urinary incontinence inthe mammal.